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Impact of Sulfatase-2 on cancer progression and prognosis in patients with renal cell carcinoma.

ABSTRACT: Heparan sulfate-specific endosulfatase-2 (SULF-2) can modulate the signaling of heparan sulfate proteoglycan-binding proteins. The involvement of SULF-2 in cancer growth varies by cancer type. The roles of SULF-2 expression in the progression and prognosis of renal cell carcinomas (RCC) have not yet been fully clarified. In the present study, the expression levels of SULF-2 mRNA and protein in 49 clinical RCC samples were determined by RT-PCR and immunostaining. The existence of RCC with higher SULF-2 expression and lower SULF-2 expression compared to the adjacent normal kidney tissues was suggested. High SULF-2 expression was correlated with an early clinical stage and less invasive pathological factors. Low SULF-2 expression was correlated with an advanced stage and higher invasive factors. Three-year cancer-specific survival (CSS) for high SULF-2 RCC and low SULF-2 RCC were 100% and 71.4%, respectively (log-rank P = 0.0019), with a significantly shorter CSS observed in low SULF-2 RCC patients. The influence of SULF-2 expression level on Wnt/VEGF/FGF signaling, cell viability and invasive properties was examined in three RCC cell lines, Caki-2, ACHN and 786-O, using a SULF-2 suppression model involving siRNA or a SULF-2 overexpression model involving a plasmid vector. High SULF-2 expression enhanced Wnt signaling and Wnt-induced cell viability, but not cell invasion. In contrast, low levels of SULF-2 expression significantly enhanced both cell invasion and viability through the activation of VEGF/FGF pathways. RCC with lower SULF-2 expression might have a higher potential for cell invasion and proliferation, leading to a poorer prognosis via the activation of VEGF and/or FGF signaling.

SUBMITTER: Kumagai S

PROVIDER: S-EPMC5132274 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Impact of Sulfatase-2 on cancer progression and prognosis in patients with renal cell carcinoma.

Kumagai Shin S Ishibashi Kei K Kataoka Masao M Oguro Toshiki T Kiko Yuichirou Y Yanagida Tomohiko T Aikawa Ken K Kojima Yoshiyuki Y

Cancer science 20161101 11

Heparan sulfate-specific endosulfatase-2 (SULF-2) can modulate the signaling of heparan sulfate proteoglycan-binding proteins. The involvement of SULF-2 in cancer growth varies by cancer type. The roles of SULF-2 expression in the progression and prognosis of renal cell carcinomas (RCC) have not yet been fully clarified. In the present study, the expression levels of SULF-2 mRNA and protein in 49 clinical RCC samples were determined by RT-PCR and immunostaining. The existence of RCC with higher ...[more]

PMID: 27589337

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Project description:BackgroundIn the clinic, how to stratify renal cell carcinoma (RCC) patients with different risks and to accurately predict their prognostic outcome remains a crucial issue. In this study, we assessed the expression and prognostic value of gankyrin in RCC patients.MethodsThe expression of gankyrin was examined in public databases and validated in specimens from two independent centers. The clinical practice and disease correlation of gankyrin in RCC were evaluated in RCC patients, various cell lines and an orthotopic RCC model.FindingsUpregulation of gankyrin expression in RCC was corroborated in two independent cohorts. High gankyrin expression positively associated with disease progression and metastasis of RCC patients. A positive correlation between gankyrin and sunitinib-resistance was also observed in RCC cell lines and in an orthotopic RCC model. Kaplan-Meier analysis revealed that patients with higher gankyrin expression presented worse prognosis of RCC patients in the two cohorts. Gankyrin served as an independent prognostic factor for RCC patients even after multivariable adjustment by clinical variables. Time-dependent AUC and Harrell's c-index analysis presented that the incorporation of the gankyrin classifier into the current clinical prognostic parameters such as TNM stage, Fuhrman nuclear grade or SSIGN score achieved a greater accuracy than without it in predicting prognosis of RCC patients. All results were confirmed in randomized training and validation sets from the two patient cohorts.InterpretationGankyrin can serve as a reliable biomarker for disease progression and for prognosis of RCC patients. Combining gankyrin with the current clinical parameters may help patient management. FUND: National Natural Science Foundation of China (No. 81773154, 81772747 and 81301861), Medical Discipline Construction Project of Pudong New Area Commission of Health and Family Planning (PWYgf2018-03), the Shanghai Medical Guidance (Chinese and Western Medicine) Science and Technology Support Project (No. 17411960200), Outstanding Leaders Training Program of Pudong Health Bureau of Shanghai (No. PWR12016-05).

Project description:Background: Kidney renal clear cell carcinoma is the most prevalent subtype of renal cell carcinoma encompassing a heterogeneous group of malignancies. Accurate subtype identification and an understanding of the variables influencing prognosis are critical for personalized treatment, but currently limited. To facilitate the sub-classification of KIRC patients and improve prognosis, this study implemented a normalization method to track cancer progression by detecting the accumulation of genetic changes that occur throughout the multi-stage of cancer development. Objective: To reveal KIRC patients with different progression based on gene expression profiles using a normalization method. The aim is to refine molecular subtyping of KIRC patients associated with survival outcomes. Methods: RNA-sequenced gene expression of eighty-two KIRC patients were downloaded from UCSC Xena database. Advanced-stage samples were normalized with early-stage to account for differences in the multi-stage cancer progression's heterogeneity. Hierarchical clustering was performed to reveal clusters that progress differently. Two techniques were applied to screen for significant genes within the clusters. First, differentially expressed genes (DEGs) were discovered by Limma, thereafter, an optimal gene subset was selected using Recursive Feature Elimination (RFE). The gene subset was subjected to Random Forest Classifier to evaluate the cluster prediction performance. Genes strongly associated with survival were identified utilizing Cox regression analysis. The model's accuracy was assessed with Kaplan-Meier (K-M). Finally, a Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed. Results: Three clusters were revealed and categorized based on patients' overall survival into short, intermediate, and long. A total of 231 DEGs were discovered of which RFE selected 48 genes. Random Forest Classifier revealed a 100% cluster prediction performance of the genes. Five genes were identified with significant diagnostic capacity. The downregulation of genes SALL4 and KRT15 were associated with favorable prognosis, while the upregulation of genes OSBPL11, SPATA18, and TAL2 were associated with favorable prognosis. Conclusion: The normalization method based on tumour progression from early to late stages of cancer development revealed the heterogeneity of KIRC and identified three potential new subtypes with different prognoses. This could be of great importance for the development of new targeted therapies for each subtype.

Dataset Information

Impact of Sulfatase-2 on cancer progression and prognosis in patients with renal cell carcinoma.

Publications

Impact of Sulfatase-2 on cancer progression and prognosis in patients with renal cell carcinoma.

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